Metastasis is the major cause of cancer-related deaths (Gupta et al., 2006). Metastatic disease may develop years or even decades after successful treatment of the primary tumor (Aguirre-Ghiso et al., 2007; Pantel et al., 2004). This prolonged latency phase occurring between treatment and disease progression is often due to tumor dormancy (Aguirre-Ghiso et al., 2007), a stage in which residual disease is present but not clinically apparent. Tumor dormancy is caused either by cell cycle arrest (Chambers et al., 2002; Townson et al., 2006) or by a balance between proliferation and cell death (Holmgren et al., 1995). Tumor progression to late relapse and frank metastasis is often due to the awakening of dormant micrometastases (Chambers et al., 2002; Pantel et al., 2007; Wikman et al., 2008).
The mechanisms that sustain dormancy and those regulating the transition from dormancy to progressive disease from micrometastases remain widely unknown (Aguirre-Ghiso et al., 2007). However, the microenvironment is thought to play a critical role in tumor growth and progression (Joyce et al., 2009; Kim et al., 2011; Witz et al., 2008; Witz et al., 2008; Witz et al., 2006) and accumulating evidence suggests that the mechanisms governing tumor dormancy and metastatic recurrence are largely regulated by the microenvironment of the distant organ in which micrometastases are present (Klein-Goldberg et al., 2014; Maman et al., 2013b; Paez et al., 2012; Wikman et al., 2008).
A notable example is neuroblastoma, the most common extracranial solid tumor in children. Despite intensive treatment regimens, 60% to 70% of children with high-risk disease will ultimately experience relapse due to the presence of neuroblastoma micrometastasis (Smith et al., 2010). Since cure after relapse of high-risk disease is extremely rare, it is a necessity to identify novel and reliable modalities for the inhibition and elimination of neuroblastoma micrometastases.
Using a xenotransplant system (Nevo et al., 2008), it was reported that human neuroblastoma cells inoculated orthotopically into the adrenal gland of nude mice migrate to the lung and form dormant micrometastases (MicroNB) (Edry Botzer et al., 2011). These dormant micrometastases persist for long periods of time without forming overt metastasis. This situation is consistent with the observation that lung metastasis in neuroblastoma patients is a relatively late event in the progression of this disease (Cowie et al., 1997; Kammen et al., 2001). The state of dormancy of the micrometastatic cells is lung-specific: MicroNB cells harvested from lungs proliferated in culture and produced local tumors when inoculated into the adrenal gland of nude mice, indicating that once removed from the restraining lung microenvironment they were able to propagate (Edry Botzer et al., 2011).
Based on these findings, it was postulated that neuroblastoma lung metastases are regulated by the lung microenvironment. Specifically, it was hypothesized that the MicroNB cells residing in the lungs are dormant at this site because of proliferation-restraining functions of the lung microenvironment. This hypothesis was confirmed by a showing that lung-derived factors significantly reduced the viability of MicroNB cells by up-regulating the expression of pro-apoptotic genes, inducing cell cycle arrest, and decreasing ERK and FAK phosphorylation in these cells (Maman et al., 2013).
The identification of specific factors that maintain dormant micrometastases or that trigger active metastatic growth from micrometastases will be important in the development of new means for detecting the presence of micrometastases and for treating and/or preventing them. The present invention is directed to these and other important goals.